Neurodegenerative disorders of both acute types (e.g. stroke, head trauma, Bell's palsy, spinal cord and other nerve crush injuries) and chronic types (e.g. Alzheimer's disease, Parkinson's disease, Picks's disease, amyotrophic lateral sclerosis, Huntington's disease, glaucoma, as well as idiopathic neuropathies) are responsible for enormous human suffering, are a burden on health care systems and result in significant economic loss. A drug or treatment which could prevent, delay or alleviate one or more of these conditions would be of immense value.
R-Deprenyl hydrochloride (selegiline, L-deprenyl) has been demonstrated to be an effective adjuvant to L-dopa in the treatment of Parkinson's disease and, in early otherwise untreated cases, it has more recently been reported to delay onset of symptoms when administered alone. It has also been claimed that the use of deprenyl improved the clinical condition of some Alzheimer patients and the symptoms of attention deficit disorder in Tourette's syndrome patients. In addition, it has been observed to prolong life span and sexual activity in rodents and humans.
Initially, the improvement in Parkinson's and other patients was ascribed to the protection of neurons by the MAO-B inhibitory properties of deprenyl. However, studies of the effect of deprenyl on neuronal survival in N-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine (MPTP)-induced Parkinsonism, axotomized immature facial motoneurons in rats, and hippocampal neuron death following ischemia or excitotoxin insult have shown that survival is increased by a mechanism which is independent of monoamine oxidase type B (MAO-B) inhibition. Studies with PC12 cells have shown that deprenyl can prevent apoptosis by a mechanism which involves selective alterations in gene expression to block the loss of mitochondrial function which in turn would commit these cells to apoptosis. Deprenyl has also been shown to prevent N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4)-induced degeneration of rat brain noradrenergic axons and terminals. The concentrations of deprenyl required to prevent apoptosis are at least an order of magnitude lower than the minimum necessary for MAO-B inhibition in some of these models. Furthermore, not all MAO-B inhibitors are effective in rescuing damaged neurons.
Deprenyl is metabolized to amphetamine and methamphetamine which have been observed to be neurotoxic even at quite low concentrations, which creates a possible problem with deprenyl as a neuronal rescue drug. Similarly deprenyl has been shown to enhance the cytotoxicity of dopamine towards catecholaminergic neuroblastoma SH-SY5Y cells. Deprenyl has been demonstrated to be a substrate for cytochrome P450 enzymes, which mediate the dealkylation process leading to the observed metabolites, methamphetamine and desmethyldeprenyl. Desmethyldeprenyl is active as an anti-apoptotic drug and studies involving the inhibition of P450 enzymes have shown that desmethyldeprenyl is the active component when deprenyl is given since pretreatment with a P450 inhibitor such as proadifen eliminates the neurorescue properties of deprenyl. It has also been reported that the desmethyldeprenyl-like compound, N-propargyl-1-aminoindan, is effective in enhancing the in vitro neuronal survival after glutamate toxicity.
Recently, some aliphatic analogues of deprenyl have proven to be as effective MAO-B inhibitors as deprenyl. As with deprenyl, it is the R-enantiomers which are active. They have also been shown to protect and rescue damaged neurons in the same models of neurodegeneration described above for deprenyl.
The aliphatic propargylamines identified in this application are active as antiapoptotic compounds.